(a) Field of the Invention
Isomers of 1-azabicyclo[2.2.2]oct-3-yl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-nitropyridine-3-carboxylate and their nontoxic acid addition salts are useful calcium agonists having utility as cardiotonics and in the treatment of cardiovascular disorders such as congestive heart failure.
(b) State of the Art
The essential role of calcium ions in the contraction of muscle has been well known since the last century. In contrast to skeletal muscle in which the actions of calcium ions occur within the cell, the operation of smooth and cardiac muscle depends to a large extent on the extracellular concentration of calcium. Therefore, the regulation of extracellular calcium plays a crucial role in the treatment of several cardiovascular disorders.
The most common agents used to regulate these ions are calcium antagonists or calcium channel blockers. Simplistically, these are compounds that "slow" the entry of calcium ions into the cell and thereby reduce the force or contractility of cardiac muscle resulting in the lowering of blood pressure. Additionally, these agents find use in the treatment of angina caused by abnormal vasoconstriction of coronary arteries and classical effort associated angina.
Another much smaller class of agents that regulate these ions are calcium agonists or calcium channel activators. These compounds promote the movement of calcium ions through the cell wall and therefore increase contractility. They may be useful in the treatment of disorders of lessened cardiac output such as congestive heart failure. Alternatively, they may be used as tools in the pharmacological study of calcium channels.
Methyl 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)-3-pyridine carboxylate [BAY K 8644, M. Schramm, G. Thomas, R. Toward and G. Frankowiak, Nature, 303, 535 (1983), German Patent DE No. 3,447,169 and European Pat. No. 186 028 A2], whose pharmacological characteristics have been thoroughly studied, is a prototype of the dihydropyridine calcium agonists. It causes potent positive inotropic effects. H. Rogg et al. [Biochem. Biophys. Res. Commun. 118: 842, 1984, European Pat. Nos. 111,453 and 111,455] have disclosed ethyl 4-[2-(difluoromethoxy)phenyl]-1,4,5,7-tetrahydro-2-methyl-5-oxofuro[3,4-b] pyridine-3-carboxylate (CGP 28392) and described its ability to increase in a dose-dependent manner the concentration of extracellular calcium ions.
The effects of stereochemistry on the biological actions of this type of pharmacological agent have been described by R. P. Hoff, U. T. Ruegg, A. Hof and A. Vogel [J. Cardiovasc. Pharmacol., 7, 689 (1985), British Pat. No. 2,148,895 and German Pat. No. 3,438 884]. Racemic 2-propyl 4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-5-nitropyridine-3-carboxylat e (202-792) enhanced contractions of rabbit aortic rings at low levels of depolarization, the typical result of calcium agonism, but inhibited contraction and radioactive calcium uptake at high levels of depolarization. The R enantiomer also inhibited contraction and radioactive calcium uptake and showed no stimulant activity. The S enantiomer, however, shifted the concentration-response curve for depolarization-induced contraction in an almost parallel fashion to the left; it enhanced contraction. This compound enhanced radioactive calcium uptake dependently at all levels of depolarization. Thus, the stereoisomers of this dihydropyridine behave as a calcium entry blocker or a calcium entry enhancer, depending on their stereochemistry.
Similar results have been described for ethyl .beta.-amino-4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3-carboxylate [H 160/51; U.S. Pat. No. 4,532,248 and German Pat. No. 3,130,041] by P. Gjorstrup, H. Harding, R. Isaksson and C. Westerlund [Eur. J. Pharmacol., 122, 357 (1986)]. The optical isomers of this dihydropyridine were found to have opposing actions in the cat papillary muscle and rat portal vein. The (+) enantiomer inhibited the actions of calcium ions and therefore decreased the force of contraction of these tissues, whereas the (-) enantiomer stimulated calcium's effects and was found to significantly increase the force of contraction.
As can easily be seen, a variety of structurally diverse dihydropyridines possess calcium agonist activity. In fact, P. Gjorstrup et al. [Eur. J. Pharmacol., 122, 357-361, (1986)] states that "The structural features responsible for a specific fit of an agonist (to the calcium channels) seem more obscure."
Relatively few calcium channel modifiers with a basic amine in the alkyl portion of a 1,4-dihydropyridine-3-carboxylic acid ester have been described. The vascular and cardiac effects of another calcium agonist 2-(2-pyridyl)ethyl-3-anilinocarbonyl-4-(2-chlorophenyl)-1,4-dihydro-2,6-di methylpyridine-3-carboxylate (YC-170), have been described by Y. Hattori, H. Nakaya, N. Tohse and M. Kanno [J. Pharmacol. Exp. Ther., 238, 670]. This agent produced a positive inotropic effect in isolated guinea pig atrium and induced contraction in isolated rabbit aortic strips. However, this agonist caused a decrease in contractile tension in the atrium partially depolarized with a low concentration of potassium and produced a relaxant effect on the aorta precontracted by a high concentration of potassium. These results indicate that YC-170 may behave not only as a calcium agonist, but also as a calcium antagonist depending on the cellular membrane potential. Esters of 1-azabicyclo[2.2.2]octan-3-ol with aryl or aralkylcarboxylic acids generally have calcium channel blocking activity (L. Noronha-Blob, C. Richard and D. C. U'Prichard, Biochem. and Biophys Res. Commun., 147, 182-188, 1987).
The novel isomers of 1-azabicyclo[2.2.2]oct-3-yl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-nitropyridine-3-carboxylate described herein are potent calcium channel agonists as evidenced by their ability to potentiate the physiological movement of calcium ions and to enhance calcium-evoked smooth muscle contractility. These actions indicate usefulness of these isomers as cardiotonic agents and in cardiac disorders such as congestive heart failure.